New promising targets to control neuropathic pain No abstract available

Virtual reality, music, and pain: developing the premise for an interdisciplinary approach to pain management No abstract available

Quantitative sensory testing and predicting outcomes for musculoskeletal pain, disability, and negative affect: a systematic review and meta-analysis Hypersensitivity due to central pain mechanisms can influence recovery and lead to worse clinical outcomes, but the ability of quantitative sensory testing (QST), an index of sensitisation, to predict outcomes in chronic musculoskeletal disorders remains unclear. We systematically reviewed the evidence for ability of QST to predict pain, disability, and negative affect using searches of CENTRAL, MEDLINE, EMBASE, AMED, CINAHL, and PubMed databases up to April 2018. Title screening, data extraction, and methodological quality assessments were performed independently by 2 reviewers. Associations were reported between baseline QST and outcomes using adjusted (β) and unadjusted (r) correlations. Of the 37 eligible studies (n = 3860 participants), 32 were prospective cohort studies and 5 randomised controlled trials. Pain was an outcome in 30 studies, disability in 11, and negative affect in 3. Meta-analysis revealed that baseline QST predicted musculoskeletal pain (mean r = 0.31, 95% confidence interval [CI]: 0.23-0.38, n = 1057 participants) and disability (mean r = 0.30, 95% CI: 0.19-0.40, n = 290 participants). Baseline modalities quantifying central mechanisms such as temporal summation and conditioned pain modulation were associated with follow-up pain (temporal summation: mean r = 0.37, 95% CI: 0.17-0.54; conditioned pain modulation: mean r = 0.36, 95% CI: 0.20-0.50), whereas baseline mechanical threshold modalities were predictive of follow-up disability (mean r = 0.25, 95% CI: 0.03-0.45). Quantitative sensory testing indices of pain hypersensitivity might help develop targeted interventions aiming to improve outcomes across a range of musculoskeletal conditions.

Do chronic pain and comorbidities affect brain function in sickle cell patients? A systematic review of neuroimaging and treatment approaches Sickle cell disease (SCD) is a medical condition in which chronic pain is common and negatively impacts psychosocial function and quality of life. Although the brain mechanisms underlying chronic pain are well studied in other painful conditions, the brain mechanisms underlying chronic pain and the associated psychosocial comorbidities are not well established in SCD. A growing literature demonstrates the effect of treatment of chronic pain, including pharmacological and nonpharmacological treatments, on brain function. The present systematic review aimed to (1) determine the effects of chronic pain and psychosocial comorbidities on brain function of patients with SCD; (2) summarize pharmacological and nonpharmacological approaches to treat these symptoms; and (3) identify areas for further investigation of potential beneficial effects of treatments on brain function. Titles were screened using predefined criteria, including SCD, and abstracts and full texts were reviewed by 2 independent reviewers. A total of 1167 SCD articles were identified, and 86 full articles were included covering 3 sections: chronic pain (4 studies), psychosocial comorbidities (11 studies), and pharmacological and nonpharmacological treatments (71 studies). Neuroimaging evidence demonstrates aberrant neural processing related to chronic pain and psychosocial comorbidities in SCD beyond ischemic stroke and cerebral hemorrhage. Although neuroimaging studies show an important role for psychological factors, pain management is nearly exclusively based on opioids. Behavior therapy seems useful to improve psychological symptoms as well as chronic pain and quality of life. Further investigation is required with larger cohorts, matched controls, and examination of treatment-related neural mechanisms.

Meta-analysis of the psychometric properties of the Pain Catastrophizing Scale and associations with participant characteristics The aims of this study were to review the psychometric properties of the widely used Pain Catastrophizing Scale (PCS) using meta-analytic methods and to investigate the relationship between PCS scores and participant characteristics. A systematic search from 1995 found 229 experimental, quasi-experimental, and correlational studies that report PCS scores. Multivariate regression explored variables related to pain catastrophizing and participant demographics. Across studies, good internal reliability (α = 0.92, 95% confidence interval 0.91-0.93) and test–retest reliability scores (Spearman ρ = 0.88, 95% confidence interval 0.83-0.93) were found for PCS total scores but not for subscales. Pain Catastrophizing Scale scores were unrelated to age or sex, but strongly related to participants' pain type, highest in those with generalized pain. Language of the PCS also affected PCS scores, with further research necessary to determine linguistic, cultural, or methodological (eg, sampling strategy) influences. Study type influenced PCS scores with nonrandomized controlled trials reporting higher PCS scores than other study types, but results were confounded with pain diagnosis, as controlled trials were more likely than quasi-experimental studies to recruit clinical samples. The meta-analytic results provide insights into demographic influences on pain catastrophizing scores and highlight areas for further research. The advantages of systematic review and meta-analytic methods to achieve greater understanding and precision of psychometric properties—in this case, of the PCS—are applicable to other widely used outcome tools.

How are pain and traumatic stress symptoms related in acute whiplash–associated disorders? An investigation of the role of pain-related fear in a daily diary study Comorbidity of pain and posttraumatic stress disorder is well recognized, but the reason for this association is unclear. This study investigated the direction of the relationship between pain and traumatic stress and the role that pain-related fear plays, for patients with acute whiplash–associated disorder. Participants (n = 99) used an electronic diary to record hourly ratings of pain, traumatic stress, and fear of pain (FOP) symptoms over a day. Relationships between pain, traumatic stress, and pain-related fear symptoms were investigated through multilevel models including variables lagged by 1 hour. Traumatic stress was associated with previous pain, even after controlling for previous traumatic stress and current pain; current pain was not associated with previous traumatic stress. The relationship between traumatic stress and previous pain became negligible after controlling for FOP, except for traumatic stress symptoms of hyperarousal that were driven directly by pain. Overall, these results support a pain primacy model, and suggest that pain-related fear is important in the maintenance and development of comorbid pain and traumatic stress symptoms. They also confirm that traumatic stress symptoms of hyperarousal are central in this relationship. Differences between this study and others that reported mutual maintenance can be understood in terms of different stages of whiplash-associated disorder and different intervals between repeated measurements. Traumatic stress may affect pain over longer time intervals than measured in this study. Future research could explore how relationships between traumatic stress symptoms, pain, and FOP change over time, and whether previous experiences of traumatic stress influence these relationships.

Cooling the skin for assessing small-fibre function In this clinical and neurophysiological study using a novel cold stimulator, we aim at investigating whether cold-evoked potentials (CEPs) may prove to be a reliable diagnostic tool to assess trigeminal small-fibre function. Using a novel device consisting of micro-Peltier elements, we recorded CEPs after stimulating the supraorbital and perioral regions and the hand dorsum in 15 healthy participants and in 2 patients with exemplary facial neuropathic pain conditions. We measured peripheral conduction velocity at the upper arm and studied the brain generators using source analysis. In healthy participants and patients, we also compared CEPs with laser-evoked potentials. In the healthy participants, cold stimulation evoked reproducible scalp potentials, similar to those elicited by laser pulses, although with a latency of about 30 ms longer. The mean peripheral conduction velocity, estimated at the upper arm, was 12.7 m/seconds. The main waves of the scalp potentials originated from the anterior cingulate gyrus and were preceded by activity in the bilateral opercular regions and bilateral dorsolateral frontal regions. Unlike laser stimulation, cold stimulation evoked scalp potential of similar amplitude across perioral, supraorbital, and hand dorsum stimulation. In patients with facial neuropathic pain, CEP recording showed the selective damage of cold pathways providing complementary information to laser-evoked potential recording. Our clinical and neurophysiological study shows that this new device provides reliable information on trigeminal small fibres mediating cold sensation and might be useful for investigating patients with facial neuropathic pain associated with a distinct damage of cold-mediating fibres.

Development and course of chronic widespread pain: the role of time and pain characteristics (the HUNT pain study) Chronic widespread pain (CWP) is common and associated with loss of functioning and health. Subjects with chronic nonwidespread pain (CnWP) are at increased risk of developing CWP, but few studies have described the nature of the development over time. We followed a random sample of 3105 participants from the population-based HUNT 3 study with 5 annual measurements of pain over 4 years. Although 29% reported CWP on at least 1 occasion, only 7% reported it consistently on 4 or 5 occasions. The average annual cumulative incidence was 5%, and the recovery rate was 38%. In mutual adjusted analysis, the risk of developing CWP from 1 year to the next was higher in subjects with chronic pain (relative risk [RR] = 2.4; 95% confidence interval [CI]: 1.8-3.4), 2 or more pain regions (RR = 3.3; 95% CI: 2.5-4.4), moderate pain or more (RR = 1.8; 95% CI: 1.5-2.6), and with comorbid chronic disease (RR = 1.6; 95% CI: 1.3-1.9). Developing CWP was associated with a modest concurrent change in self-reported mental and physical health. The risk of developing CWP between the fourth and fifth occasions was 80% lower for subjects without a history of CWP, compared to those with a history of CWP. For subjects without previous CWP, the development was associated with previously reported CnWP, but not with the number of occasions with CnWP, in analyses adjusted for sex, age, and pain severity. A substantial proportion of the new cases of CWP originates from subjects floating below and above the definition for CWP over time and, thus, does not seem to involve major transitions in health.

High-threshold primary afferent supply of spinal lamina X neurons The spinal gray matter region around the central canal, lamina X, is critically involved in somatosensory processing and visceral nociception. Although several classes of primary afferent fibers terminate or decussate in this area, little is known about organization and functional significance of the afferent supply of lamina X neurons. Using the hemisected ex vivo spinal cord preparation, we show that virtually all lamina X neurons receive primary afferent inputs, which are predominantly mediated by the high-threshold Aδ- fibers and C-fibers. In two-thirds of the neurons tested, the inputs were monosynaptic, implying a direct targeting of the population of lamina X neurons by the primary nociceptors. Beside the excitatory inputs, 48% of the neurons also received polysynaptic inhibitory inputs. A complex pattern of interactions between the excitatory and inhibitory components determined the output properties of the neurons, one-third of which fired spikes in response to the nociceptive dorsal root stimulation. In this respect, the spinal gray matter region around the central canal is similar to the superficial dorsal horn, the major spinal nociceptive processing area. We conclude that lamina X neurons integrate direct and indirect inputs from several types of thin primary afferent fibers and play an important role in nociception.

Antibodies binding the head domain of P2X4 inhibit channel function and reverse neuropathic pain P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting P2X4 have been unsuccessful largely because of the difficulty in engineering specificity and selectivity. Here, we describe for the first time the generation of a panel of diverse monoclonal antibodies (mAbs) to human and mouse P2X4, capable of both positive and negative modulation of channel function. The affinity-optimised anti-P2X4 mAb IgG#151-LO showed exquisite selectivity for human P2X4 and induced potent and complete block of P2X4 currents. Site-directed mutagenesis of P2X4 revealed the head domain as a key interaction site for inhibitory mAbs. Inhibition of spinal P2X4 either by intrathecal delivery of an anti-P2X4 mAb or by systemic delivery of an anti-P2X4 bispecific mAb with enhanced blood–spinal cord barrier permeability produced long-lasting (>7 days) analgesia in a mouse model of neuropathic pain. We therefore propose that inhibitory mAbs binding the head domain of P2X4 have therapeutic potential for the treatment of neuropathic pain.